CVM-1118 and Sorafenib Combination in Subjects With Advanced Hepatocellular Carcinoma

• ClinicalTrials.gov Identifier: NCT03582618
• Recruitment Status: Active, not recruiting
• First Posted: July 11, 2018
• Last Update Posted: January 26, 2022
• Sponsor: TaiRx, Inc.
• Information provided by (Responsible Party): TaiRx, Inc.

Tracking Information

• First Submitted Date: May 21, 2018
• First Posted Date: July 11, 2018
• Last Update Posted Date: January 26, 2022
• Actual Study Start Date: July 12, 2018
• Actual Primary Completion Date: November 16, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 9, 2018)

Objective Response Rate (ORR) [ Time Frame: 24 weeks after the last subject starts CVM-1118 ]

Assessment by modified RECIST criteria

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: July 9, 2018)

• Overall survival (OS) [ Time Frame: 24 weeks after the last subject starts CVM-1118 and up to 1 year after the last-dose ]
  Overall survival (OS) is defined as time from first dose of study drug to death
• Progression-free survival (PFS) [ Time Frame: 24 weeks after the last subject starts CVM-1118 and up to 1 year after the last-dose ]
  Progression-free survival (PFS) is defined as time from the first dose of study drug to the time of progression or death
• Time to progression (TTP) [ Time Frame: 24 weeks after the last subject starts CVM-1118 and up to 1 year after the last-dose ]
  Time to progression (TTP) is defined as the time from the first dose of study drug to the time of progression
• Duration of response (DoR) [ Time Frame: 24 weeks after the last subject starts CVM-1118 and up to 1 year after the last-dose ]
  Duration of response (DoR) is defined as time from the first documentation of response to the time of progression
• Disease control rate (DCR) [ Time Frame: 24 weeks after the last subject starts CVM-1118 and up to 1 year after the last-dose ]
  Disease control rate (DCR) is defined as the sum of complete response (CR), partial response (PR), and stable disease rate (SD) as assessed by modified RECIST criteria
• Rate of Adverse event (AE) and Serious Adverse Event (SAE) [ Time Frame: During the course of trial and within 28 days following the last dose of CVM-1118 or prior to the start of new treatment, whichever comes first ]
  Rate of Adverse event (AE) and Serious Adverse Event (SAE) are assessed using Common Terminology Criteria for Adverse Events v5 (CTCAE) criteria
• Assessed the baseline and out-of-range vital signs_ body temperature, blood pressure, heart rate, and respiratory rate by CTCAE v4.03 [ Time Frame: During the course of trial and within 28 days following the last dose of CVM-1118 or prior to the start of new treatment, whichever comes first ]
  A list of all laboratory normal ranges will also be provided. Values with CTCAE v4.03 Grade ≧ 3 will be identified with flags.
• Assessed the baseline and out-of range laboratory parameters_hematology, chemistry, coagulation, and urinalysis by CTCAE v4.03 [ Time Frame: During the course of trial and within 28 days following the last dose of CVM-1118 or prior to the start of new treatment, whichever comes first ]
  A list of all laboratory normal ranges will also be provided. Values with CTCAE v4.03 Grade ≧ 3 will be identified with flags.
• Abnormalities in electrocardiography (ECG) [ Time Frame: During the course of trial and within 28 days following the last dose of CVM-1118 or prior to the start of new treatment, whichever comes first ]
  a 12-lead (with a 10-second rhythm strip) tracing, with a capacity to calculate the standard intervals automatically, will be used.
• Maximum Plasma Concentration [Cmax] of sorafenib, CVM-1118, and its metabolite CVM-1125 after CVM-1118 dosing [ Time Frame: During Cycle 1 and Cycle 2 (each cycle is 28 days) ]
  Maximum Plasma Concentration [Cmax] of sorafenib, CVM-1118, and its metabolite CVM-1125 will be measured to see maximum exposure after CVM-1118 dosing
• Area Under the Curve [AUC] of sorafenib, CVM-1118, and its metabolite CVM-1125 after CVM-1118 dosing [ Time Frame: During Cycle 1 and Cycle 2 (each cycle is 28 days) ]
  Area Under the Curve [AUC] of sorafenib, CVM-1118, and its metabolite CVM-1125 will be measured to see drug exposure after CVM-1118 dosing
• Pharmacodynamics analysis for the relationship of Cmax and ORR [ Time Frame: During Cycle 1 and Cycle 2 (each cycle is 28 days) ]
  Relationship between Cmax and ORR will be evaluated
• Pharmacodynamics analysis for the relationship of AUC and ORR [ Time Frame: During Cycle 1 and Cycle 2 (each cycle is 28 days) ]
  Relationship between AUC and ORR will be evaluated
• Pharmacodynamics analysis for the relationship of Cmax and Adverse Event (AE) [ Time Frame: During Cycle 1 and Cycle 2 (each cycle is 28 days) ]
  Relationship between Cmax and AE will be evaluated
• Pharmacodynamics analysis for the relationship of AUC and Adverse Event (AE) [ Time Frame: During Cycle 1 and Cycle 2 (each cycle is 28 days) ]
  Relationship between AUC and AE will be evaluated

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: CVM-1118 and Sorafenib Combination in Subjects With Advanced Hepatocellular Carcinoma
• Official Title: A Phase 2, Open-Label Study With Orally Administered CVM-1118 and Sorafenib in Subjects With Advanced Hepatocellular Carcinoma
• Brief Summary: CVM-1118 is a new small molecule chemical entity being developed as a potential anti-cancer therapeutic by TaiRx, Inc. CVM-1118 is a potent anti-cancer agent in numerous human cancer cell lines. The safety of administrating CVM-1118 on human is evaluated from the phase 1 study. The objectives of the phase 2 study is to further investigate the efficacy of CVM-1118 with sorafenib for subjects with advanced hepatoma.

Detailed Description

Sorafenib is a multi-kinase inhibitor that inhibits tumor growth and angiogenesis. Although sorafenib is the first-line treatment of advanced hepatocellular cancer (HCC), patients developing resistance to sorafenib have been reported.

To meet the medical need, TaiRx, Inc. develops a new small molecule drug, CVM-1118 targeting the formation of vasculogenic mimicry (VM). VM has been associated with tumor metastasis and poor clinical outcomes. VM is reported to be particularly active in tumor under hypoxia state when patients are treated with the potent vascular endothelial growth factor (VEGF) inhibitor like sorafenib. Hence, the ability of inhibiting the VM network make CVM-1118 a potential good combination drug with sorafenib for advanced diseases.

The safety profile of CVM-1118 dosing has been established in the phase 1 study. The analysis of metabolism pathways further showed that the potential of CVM-1118 and sorafenib drug-drug interactions are very low.

Based on the mechanism of actions and the safety analysis of sorafenib and CVM-1118, the design of phase 2 trial with the combination therapy might have great potential for the patients with advanced HCC.

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Hepatocellular Carcinoma
• Advanced Cancer

Intervention

• Drug: Sorafenib
  Sorafenib will be administered orally at a starting dose of 400mg BID daily and the necessity of dose reduction will be assessed during sorafenib tolerability assessment period
  Other Name: Nexavar
• Drug: CVM-1118
  CVM-1118 will be administered orally at 150 mg BID or 200 mg BID daily and combined with the tolerable dose of sorafenib for a 28-day cycle
  Other Name: TRX-818

Study Arms

Experimental: Sorafenib + CVM-1118

Cycle 0 (at least 3 weeks): sorafenib tolerability assessment period (sorafenib alone)

400mg BID daily (starting dose); The subject will be assessed for the need for a dose reduction in sorafenib during this period.

Cycle 1+ (28-day cycles): combination period (sorafenib+CVM-1118)

Tolerable dose of sorafenib and CVM-1118 150 (starting dose) or 200 mg BID will be administered continuously for a 28-day cycle until progressive disease, unacceptable toxicity, or consent withdrawal.

Interventions:

• Drug: Sorafenib
• Drug: CVM-1118

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Estimated Enrollment (submitted: July 9, 2018): 40
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: March 2022
• Actual Primary Completion Date: November 16, 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Signed, informed consent
2. Age 18 or older (for all treatment locations with exception of Taiwan), or age 20 or older (Taiwan only)
3. Pathologically or cytologically-confirmed, advanced-stage hepatocellular carcinoma without prior systemic treatment except for prior immunotherapy and Child-Pugh liver function class A appropriate for treatment with sorafenib
4. Measurable disease according to modified Response Evaluation Criteria in Solid Tumors criteria (mRECIST)
5. Eastern Cooperative Oncology Group (ECOG) performance status: 0 to 1

6. Adequate laboratory parameters including:

   1. Serum aspartate transaminase (AST) and serum alanine transaminase (ALT) ≤ 3.0 x upper limit of normal (ULN), or AST and ALT ≤ 5.0 x ULN if liver function abnormalities are due to underlying malignancy
   2. Total serum bilirubin ≤ 2.0 x ULN (except for subjects with documented Gilbert's syndrome who have a limit of ≤ 3.0 x ULN)
   3. Absolute neutrophil count (ANC):1500/µL
   4. Platelets: 90,000/µL
   5. Hemoglobin: 9.0 g/dL
   6. Serum creatinine ≤ 2.0 x ULN or creatinine clearance of ≥ 50 mL/min
   7. Serum albumin ≥ 3.0 g/dL
   8. International normalized ratio (INR) ≤ 1.4
   9. Prothrombin Time (PT)/ Activated Partial Thromboplastin Time (aPTT) ≤ 1.2 x ULN
7. QTc interval (using Fridericia correction) of ≤ 470 msec (QTc interval may be derived from up to 3 separate EKGs performed at least 5 minutes apart)
8. Willingness to participate in collection of pharmacokinetic and other exploratory blood collection as defined in the protocol
9. Willingness to use adequate contraception throughout study and for a period of 3 months after last dose of CVM-1118

Exclusion Criteria:

1. Major surgery (other than diagnostic surgery) or radiation therapy within 28 days of starting study treatment
2. Prior systemic immunotherapy for hepatoma within 28 days of starting study treatment
3. Systemic anticancer therapy (e.g., chemotherapy, hormonal, investigational, biological therapies) within 28 days (or fewer than 5 half-lives, whichever is shorter) of starting study treatment except for ongoing hormonal therapy administered for control of a second cancer (e.g., breast or prostate cancer)
4. Receipt of a CYP3A4 inducer less than 28 days or 5 half-lives of the CYP3A4 inducer prior to the first day of sorafenib administration
5. Other known active cancer(s) likely to require treatment in the next two (2) years or likely to impact the assessment of any study endpoints
6. Active, uncontrolled bacterial, viral, or fungal infection(s) requiring systemic therapy (e.g., subjects with known HBV or HCV infections controlled on antivirals are allowed)
7. Known Central Nervous system (CNS) metastases unless appropriately treated and neurologically stable for ≥ 4 weeks off steroids
8. Pregnant or currently breast-feeding
9. Known HIV-positive
10. Patients with impaired gastrointestinal (GI) diseases that may significantly alter the absorption of oral medications
11. Psychiatric illness/social situations that would interfere with compliance with study requirements
12. History of clinically significant cardiovascular abnormalities such as uncontrolled hypertension, congestive heart failure (New York Heart Association classification ≥ 2), unstable angina, poorly controlled arrhythmias, myocardial infarction within 6 months of study entry
13. Other severe acute or chronic medical or psychiatric conditions or laboratory abnormalities that would impart, in the judgement of the PI and/or Sponsor, excess risk associated with study participation or study drug administration, which would make the subject inappropriate for entry into this study

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Taiwan, United States

Administrative Information

• NCT Number: NCT03582618
• Other Study ID Numbers: CVM-004
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: TaiRx, Inc.
• Original Responsible Party: Same as current
• Current Study Sponsor: TaiRx, Inc.
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: TaiRx, Inc.
• Verification Date: January 2022